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Airway hyperresponsiveness in mice with targeted deletion of the Tachykinin I gene.

Neurokinins (NK's) are involved in the development of bronchial inflammation and airway hyperresponsiveness. The TAC1 knockout mouse (TAC1-/-), in which the tachykinin l gene encoding for the NK's substance P (SP) and neurokinin A (NKA) is ill eliminated through targeted gene disruption, provides a novel model in which to study the effects of NK's on airway function. We investigated airway responsiveness to methacholine pl (Mch, 10-320ug/kg i.v.) in 10 TAC1-/- and 10 wildtype mice (TAC1+/+). Baseline resistance (R)and elastance did not differ between groups, but the log [Mch] required to increase R to twice the baseline value was significantly lower in TAC1-/- (1.93 +/-0.18 vs 2.07 +/-0.12, p<0.05). To determine if differences in responsiveness between TAC1+/+ and -/-mice were due to NK receptor stimulation by released NK's during Mch challenge, NK1 and NK2 selective antagonists(CP 99994 and SR48968 respectively, 0.5 mg/kg i.v.) (n=7) or vehicle (n=7) were administered to TAC 1 +/+ mice prior to Mch challenge. NK receptor blockade did not affect responsiveness to Mch. To determine if differences in in vivo responsiveness were related to differences in contractility of airway smooth muscle, we measured Ca2+ mobilization in response to 10 uM 5-hydroxytryptamine(5-HT) and SP in cultured tracheal smooth muscles cells from TAC1-/- and +/+ mice. 5HT and SP increased intracellular Ca2+ in both groups, with no significant differences in peak [Ca2+] between groups (peak [Ca2+] to 5HT=319 +/-78 vs 532 +/-161 nM for TAC1-/- and +/+ and 61 +/- 8 vs 60 +/-3 in response to SP). We conclude that the absence of the tachykinin l gene results in airway hyperresponsiveness but not increased airway smooth muscle contractility. Hyperresponsiveness was not mimicked by NK receptor blockade in wildtype animals.